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Frequent Aberrant Methylation of the CDH4 Gene Promoter in Human Colorectal and Gastric Cancer

¹ Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy; ² Istituto Oncologico Veneto, International Cancer Center, Molecular Biology Laboratories, Rovigo, Italy; ³ Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania; ⁴ Department of Medicine, Section of Gastroenterology, University Hospital of Ferrara, Ferrara, Italy; ⁵ Department of Surgical, Anesthesiology and Radiology Sciences, University of Ferrara, Ferrara, Italy; ⁶ Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy; ⁷ Division of Medical Oncology, Hospital S. Maria della Misericordia, Rovigo, Italy; and ⁸ Interdepartment Center for Cancer Research, University of Ferrara, Ferrara, Italy

Gene promoter methylation causes loss of tumor suppressor genes function in human cancer. Here, we show that the CDH4 gene, a member of the cadherin family encoding for R-cadherin, contains a CpG island located at the 5' of the first exon, which functions as a promoter element and is frequently affected by methylation in human cancer. By using methylation-specific PCR and reverse transcription-PCR in human cancer cell lines, promoter methylation could be directly linked to loss of gene expression. After treatment with the demethylating agent 5-aza-2-deoxycytidine, expression could be restored. Analysis of human primary tumors revealed that the CDH4 gene is methylated in 78% (38 of 49) of colorectal and 95% (20 of 21) of gastric carcinomas. CDH4 methylation was not detected in nonneoplastic colonic (0 of 10) and stomach (0 of 10) tissues or in peripheral blood (0 of 17). CDH4 methylation was detected in histologically normal tissues located in proximity of the neoplasms, indicating that CDH4 methylation is an early event in gastrointestinal tumor progression. We also proved that CDH4 methylation can be revealed in the peripheral blood of cancer patients. Our results indicate that CDH4 may act as a tumor suppressor gene in human gastrointestinal tumors and can potentially be used as an early diagnostic marker for gastrointestinal tumorigenesis.

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